Diabetes is a group of metabolic diseases characterized by high levels of blood glucose levels (≧126 mg/dL or 7.0 mmol/L). The three most common forms of diabetes are type-1 diabetes (T1D), type-2 diabetes (T2D), and gestational diabetes. T1D, also known as insulin-dependent diabetes mellitus (IDDM), is caused by the autoimmune destruction of insulin producing pancreatic beta-cells leading to total deficiency of insulin, requiring patients with T1D to take insulin by either injection or pump. Gestational diabetes is developed when pregnant women become intolerant to glucose. Gestational diabetes requires treatment to maintain appropriate blood glucose levels in order to avoid complications in the infant.
Nearly 25.8 million people in the United States have diabetes and T2D accounts for 90 to 95 percent of diagnosed diabetes. Diabetes is the leading cause of kidney failure, non-traumatic lower-limb amputation, and new cases of blindness among adults in the United States. People with diabetes are also two to four times more likely than people without diabetes to develop heart disease.
T2D, previously known as non-insulin-dependent diabetes mellitus (NIDDM), develops as peripheral cells do not use insulin properly and then the pancreas loses its ability to produce enough insulin. Under current criteria, T2D is diagnosed when fasting plasma glucose is ≧126 mg/dL (7.0 mmol/L); or plasma glucose level is ≧200 mg/dL (11.1 mmol/L) at 2-hours post-glucose load of 75 g; or an A1C level≧6.5%.
Prediabetes, also referred as impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), is a precursor condition to T2D. Prediabetes is diagnosed when fasting plasma glucose is between 100 to 125 mg/dL (5.56-6.94 mmol/L); or plasma glucose level is between 140 to 199 mg/dL (7.78-11.06 mmol/L) at 2-hours post-glucose load of 75 g; or an A1C level between 5.7 and 6.4%. Without intervention and appropriate treatment, people with prediabetes are at risk for developing T2D.
Lysophospholipids (LPs), including lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), are a group of phospholipid-derived lipid mediators and have growth factor-like effects to stimulate cell proliferation and survival through a group of G-protein coupled receptors (GPCRs), known as S1P receptors (S1P1-5). Levels of LPs are significantly increased during human pregnancy, a physiological condition under which pancreatic beta-cell mass is expanded to produce enough insulin keeping blood glucose in a normal range. Therefore, an LP analog was screened in ex vivo islets and in the db/db mice for its ability of expanding beta-cell mass. The db/db mouse is a widely used T2D animal model that exhibits severe depletion of insulin-producing beta-cells of the pancreatic islets. In this invention, it is demonstrated that oral administration of FTY720 to db/db mice normalizes fasting blood glucose by increasing beta-cell mass and blood insulin levels without affecting insulin sensitivity.
FTY720 is derived from the myriocin (ISP-1) metabolite of the fungus Isaria sinclairii and originally proposed as an anti-rejection medication indicated after transplantation. It is a structural analog of sphingosine and in vivo is phosphorylated by sphingosine kinase II to form FTY720-phosphate (FTY720-P). S1P1 plays a key role in the immune system, regulating lymphocyte egress from lymphoid tissues into the circulation. Binding of FTY720-P to S1P1 down regulates and degrades the S1P1 in lymphocytes. Therefore, FTY720 can sequester lymphocytes in lymph nodes, preventing them from moving to the central nervous system for autoimmune responses in Multiple Sclerosis. At present, FTY720 (trade name GILENYA®, generic name fingolimod) is FDA approved and is marketed by Novartis for the treatment of patients with relapsing multiple sclerosis (MS). Loss of insulin-producing beta-cell mass is a central component in the pathogenesis of T2D. Pancreatic beta-cells can modulate their mass in response to a variety of physiological and pathophysiological cues. Although some anti-diabetic drugs may positively affect beta-cells, there are few effective therapeutic approaches proposed to target beta-cell mass expansion. Therefore, there is a need for effective drugs and therapeutic methods that can preserve and increase the mass of functional beta-cells in patients with prediabetes or T2D.